Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency

Huw B. Thomas; Leigh A. M. Demain; Alfredo Cabrera-Orefice; Isabelle Schrauwen; Hanan E. Shamseldin; Alessandro Rea; Thashi Bharadwaj; Thomas B. Smith; Monika Oláhová; Kyle Thompson; Langping He; Namanpreet Kaur; Anju Shukla; Musaad Abukhalid; Muhammad Ansar; Sakina Rehman; Saima Riazuddin; Firdous Abdulwahab; Janine M. Smith; Zornitza Stark; Hanifenur Mancilar; Sait Tumer; Fatma N. Esen; Eyyup Uctepe; Vehap Topcu; Ahmet Yesilyurt; Erum Afzal; Mehri Salari; Christopher Carroll; Giovanni Zifarelli; Peter Bauer; Deniz Kor; Fatma D. Bulut; Henry Houlden; Reza Maroofian; Samantha Carrera; Wyatt W. Yue; Kevin J. Munro; Fowzan S. Alkuraya; Peter Jamieson; Zubair M. Ahmed; Suzanne M. Leal; Robert W. Taylor; Ilka Wittig; Raymond T. O'Keefe; William G. Newman

doi:10.1016/j.ajhg.2025.02.005

Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency

Huw B. Thomas, Leigh A. M. Demain, Alfredo Cabrera-Orefice, Isabelle Schrauwen, Hanan E. Shamseldin, Alessandro Rea, Thashi Bharadwaj, Thomas B. Smith, Monika Oláhová, Kyle Thompson, Langping He, Namanpreet Kaur, Anju Shukla, Musaad Abukhalid, Muhammad Ansar, Sakina Rehman, Saima Riazuddin, Firdous Abdulwahab, Janine M. Smith, Zornitza StarkHanifenur Mancilar, Sait Tumer, Fatma N. Esen, Eyyup Uctepe, Vehap Topcu, Ahmet Yesilyurt, Erum Afzal, Mehri Salari, Christopher Carroll, Giovanni Zifarelli, Peter Bauer, Deniz Kor, Fatma D. Bulut, Henry Houlden, Reza Maroofian, Samantha Carrera, Wyatt W. Yue, Kevin J. Munro, Fowzan S. Alkuraya, Peter Jamieson, Zubair M. Ahmed, Suzanne M. Leal, Robert W. Taylor, Ilka Wittig, Raymond T. O'Keefe^*, William G. Newman^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly, and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small mitochondrial ribosomal subunits and a more pronounced reduction of the large mitochondrial ribosomal subunits. There was no evidence of altered mitoribosomal assembly. The reductions in levels of oxidative phosphorylation (OXPHOS) enzyme complexes I and IV are consistent with a form of COXPD associated with bi-allelic MRPL49 variants, expanding the understanding of how disruption of the mitochondrial ribosomal large subunit results in multisystem phenotypes.

Original language	English
Pages (from-to)	952-962
Number of pages	12
Journal	American Journal of Human Genetics
Volume	112
Issue number	4
Early online date	4 Mar 2025
DOIs	https://doi.org/10.1016/j.ajhg.2025.02.005
Publication status	Published - 3 Apr 2025

Keywords

learning disability
sensorineural hearing loss
Perrault syndrome
leukodystrophy
rare disease
MRPL49
combined oxidative phosphorylation deficiency
mitochondria
mitoribosome
primary ovarian insufficiency

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Thomas, H. B., Demain, L. A. M., Cabrera-Orefice, A., Schrauwen, I., Shamseldin, H. E., Rea, A., Bharadwaj, T., Smith, T. B., Oláhová, M., Thompson, K., He, L., Kaur, N., Shukla, A., Abukhalid, M., Ansar, M., Rehman, S., Riazuddin, S., Abdulwahab, F., Smith, J. M., ... Newman, W. G. (2025). Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency. American Journal of Human Genetics, 112(4), 952-962. https://doi.org/10.1016/j.ajhg.2025.02.005

@article{0ca215c8aa314ceba35c76a88d6496b5,

title = "Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency",

abstract = "Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly, and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small mitochondrial ribosomal subunits and a more pronounced reduction of the large mitochondrial ribosomal subunits. There was no evidence of altered mitoribosomal assembly. The reductions in levels of oxidative phosphorylation (OXPHOS) enzyme complexes I and IV are consistent with a form of COXPD associated with bi-allelic MRPL49 variants, expanding the understanding of how disruption of the mitochondrial ribosomal large subunit results in multisystem phenotypes.",

keywords = "learning disability, sensorineural hearing loss, Perrault syndrome, leukodystrophy, rare disease, MRPL49, combined oxidative phosphorylation deficiency, mitochondria, mitoribosome, primary ovarian insufficiency",

author = "Thomas, \{Huw B.\} and Demain, \{Leigh A. M.\} and Alfredo Cabrera-Orefice and Isabelle Schrauwen and Shamseldin, \{Hanan E.\} and Alessandro Rea and Thashi Bharadwaj and Smith, \{Thomas B.\} and Monika Ol{\'a}hov{\'a} and Kyle Thompson and Langping He and Namanpreet Kaur and Anju Shukla and Musaad Abukhalid and Muhammad Ansar and Sakina Rehman and Saima Riazuddin and Firdous Abdulwahab and Smith, \{Janine M.\} and Zornitza Stark and Hanifenur Mancilar and Sait Tumer and Esen, \{Fatma N.\} and Eyyup Uctepe and Vehap Topcu and Ahmet Yesilyurt and Erum Afzal and Mehri Salari and Christopher Carroll and Giovanni Zifarelli and Peter Bauer and Deniz Kor and Bulut, \{Fatma D.\} and Henry Houlden and Reza Maroofian and Samantha Carrera and Yue, \{Wyatt W.\} and Munro, \{Kevin J.\} and Alkuraya, \{Fowzan S.\} and Peter Jamieson and Ahmed, \{Zubair M.\} and Leal, \{Suzanne M.\} and Taylor, \{Robert W.\} and Ilka Wittig and O'Keefe, \{Raymond T.\} and Newman, \{William G.\}",

year = "2025",

month = apr,

day = "3",

doi = "10.1016/j.ajhg.2025.02.005",

language = "English",

volume = "112",

pages = "952--962",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

}

Thomas, HB, Demain, LAM, Cabrera-Orefice, A, Schrauwen, I, Shamseldin, HE, Rea, A, Bharadwaj, T, Smith, TB, Oláhová, M, Thompson, K, He, L, Kaur, N, Shukla, A, Abukhalid, M, Ansar, M, Rehman, S, Riazuddin, S, Abdulwahab, F, Smith, JM, Stark, Z, Mancilar, H, Tumer, S, Esen, FN, Uctepe, E, Topcu, V, Yesilyurt, A, Afzal, E, Salari, M, Carroll, C, Zifarelli, G, Bauer, P, Kor, D, Bulut, FD, Houlden, H, Maroofian, R, Carrera, S, Yue, WW, Munro, KJ, Alkuraya, FS, Jamieson, P, Ahmed, ZM, Leal, SM, Taylor, RW, Wittig, I, O'Keefe, RT & Newman, WG 2025, 'Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency', American Journal of Human Genetics, vol. 112, no. 4, pp. 952-962. https://doi.org/10.1016/j.ajhg.2025.02.005

TY - JOUR

T1 - Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency

AU - Thomas, Huw B.

AU - Demain, Leigh A. M.

AU - Cabrera-Orefice, Alfredo

AU - Schrauwen, Isabelle

AU - Shamseldin, Hanan E.

AU - Rea, Alessandro

AU - Bharadwaj, Thashi

AU - Smith, Thomas B.

AU - Oláhová, Monika

AU - Thompson, Kyle

AU - He, Langping

AU - Kaur, Namanpreet

AU - Shukla, Anju

AU - Abukhalid, Musaad

AU - Ansar, Muhammad

AU - Rehman, Sakina

AU - Riazuddin, Saima

AU - Abdulwahab, Firdous

AU - Smith, Janine M.

AU - Stark, Zornitza

AU - Mancilar, Hanifenur

AU - Tumer, Sait

AU - Esen, Fatma N.

AU - Uctepe, Eyyup

AU - Topcu, Vehap

AU - Yesilyurt, Ahmet

AU - Afzal, Erum

AU - Salari, Mehri

AU - Carroll, Christopher

AU - Zifarelli, Giovanni

AU - Bauer, Peter

AU - Kor, Deniz

AU - Bulut, Fatma D.

AU - Houlden, Henry

AU - Maroofian, Reza

AU - Carrera, Samantha

AU - Yue, Wyatt W.

AU - Munro, Kevin J.

AU - Alkuraya, Fowzan S.

AU - Jamieson, Peter

AU - Ahmed, Zubair M.

AU - Leal, Suzanne M.

AU - Taylor, Robert W.

AU - Wittig, Ilka

AU - O'Keefe, Raymond T.

AU - Newman, William G.

PY - 2025/4/3

Y1 - 2025/4/3

N2 - Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly, and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small mitochondrial ribosomal subunits and a more pronounced reduction of the large mitochondrial ribosomal subunits. There was no evidence of altered mitoribosomal assembly. The reductions in levels of oxidative phosphorylation (OXPHOS) enzyme complexes I and IV are consistent with a form of COXPD associated with bi-allelic MRPL49 variants, expanding the understanding of how disruption of the mitochondrial ribosomal large subunit results in multisystem phenotypes.

AB - Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly, and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small mitochondrial ribosomal subunits and a more pronounced reduction of the large mitochondrial ribosomal subunits. There was no evidence of altered mitoribosomal assembly. The reductions in levels of oxidative phosphorylation (OXPHOS) enzyme complexes I and IV are consistent with a form of COXPD associated with bi-allelic MRPL49 variants, expanding the understanding of how disruption of the mitochondrial ribosomal large subunit results in multisystem phenotypes.

KW - learning disability

KW - sensorineural hearing loss

KW - Perrault syndrome

KW - leukodystrophy

KW - rare disease

KW - MRPL49

KW - combined oxidative phosphorylation deficiency

KW - mitochondria

KW - mitoribosome

KW - primary ovarian insufficiency

UR - https://www.scopus.com/pages/publications/105000989481

U2 - 10.1016/j.ajhg.2025.02.005

DO - 10.1016/j.ajhg.2025.02.005

M3 - Article

C2 - 40043708

SN - 0002-9297

VL - 112

SP - 952

EP - 962

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency

Abstract

Keywords

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